tbuckley/cabot-search huggingface dataset:
Raising the level of cancer care: Feasibility and reported benefit of a virtual tumor board.
Authors: Lauren Chiec, Naomi Dempsey, Mohit Shiv Agarwal, John R Ogden, James R. Broughman, Zachary Mayo, Erin Shonkwiler, Michael Chaby, Mark A. Socinski, Mark D. Pegram, Mehmet Asim Bilen, Christopher Hanyoung Lieu, Reni Butler, Michael J. Thirman, William John Gradishar, Ajay K. Nooka, Benjamin Philip Levy, Alexandra Drakaki, Susan F. Slovin, Mohammad Jahanzeb
Journal: Journal of Clinical Oncology (2022)

e18595 Background: Multidisciplinary tumor boards (TBs) are a key component of high-quality oncology care. Access is variable, particularly outside the academic setting, and limited access likely disproportionately impacts underserved patient populations and may contribute to healthcare disparities. Virtual tumor boards (VTBs) may provide a solution. Methods: Objectives of this endeavor are to test the feasibility of conducting VTBs and assess their perceived benefit and educational value. Expert US faculty formed VTB panels via an online platform to discuss complex cases submitted by clinicians. Each panel included a moderator and a radiologist, as well as a medical, radiation and surgical oncologist. After the panel discussion, written recommendations and video recordings (de-identified) were shared with submitters. Recordings were available online to viewers with embedded questions to assess learning. Submitters were surveyed as to their perceived benefit of the discussion. Viewers were surveyed to assess the educational value. Results: From 07/2020-12/2021, 323 cases (97 breast, 109 thoracic, 49 gastrointestinal, 37 genitourinary, 31 hematologic) were submitted by 48 clinicians to 38 VTBs. Submitters were surveyed with a 73% response rate; 100% reported they were likely to submit a future case for discussion and that they believe the VTB will improve care for patients. Viewers (n = 39) were surveyed with a 72% response rate and included trainees and APPs working in medical, radiation, and surgical oncology as well as radiology. All viewers endorsed that the videos were a good educational resource, and that they would use them in the future. Both embedded questions were answered 74% of the time (315/425); answers post-viewing changed 43% of the time (137/315). Conclusions: VTBs are feasible and lead to a high degree of satisfaction among case submitters. In this cohort, users reported that their patient management changed based on the discussion. Of those who discussed the case at their own TB, most felt that the VTB expanded upon prior recommendations. A large proportion of users stated that their case was not discussed at an internal TB, suggesting the VTB may address an unmet need. Those who watched the videos found them to be a good resource and would use them in the future. Data from larger cohorts will be key in understanding the full impact of this endeavor, particularly in helping to address healthcare disparities.[Table: see text]
MODL-31. Novel in vivo models of post-radiation recurrent pediatric high-grade glioma show increased susceptibility to MAPK inhibition
Authors: Aaron Knox, John DeSisto, Sarah Nelson-Taylor, Philip Coleman, Benjamin Van Court, Andrew Donson, Sana Karam, Adam Green
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer mortality, with median survival of less than one year. The standard of care for pHGG includes radiation therapy (RT), but almost all patients who respond initially relapse with aggressive, radiation-resistant disease. Matched primary/recurrent models and effective therapies for recurrent pHGG have not been adequately developed. METHODS: Orthotopic patient derived xenograft (PDX) models of radiation-resistant pHGG were developed by implanting BT245 (H3K27M) and HSJD-GBM-001 (GBM1, H3-wt) cells into mice. Resultant tumors were irradiated at 8Gy (4Gy x 2d) and allowed to regrow. Recurrent, radiation-resistant tumors (BT245MR and GBM1MR) and initial tumors (BT245M and GBM1M) were collected for bulk RNA-Seq analysis and ex vivo cell culture. Dose-response experiments were conducted in explant cells to identify drugs with increased effectiveness against recurrent (MR) cell lines versus wild-type cell lines. RESULTS: In both BT245 and GBM1 explant cells, geneset enrichment analysis (GSEA) showed upregulated mesenchymal (BT245MR: NES=3.4, FDR=0; GBM1MR: NES=2.4, FDR&amp;lt;0.002) and hypoxia-related (BT245MR: NES=3.6, FDR=0; GBM1MR: NES=3.4, FDR=0) pathways. GBM1MR tumors also showed enrichment in MAPK signaling (NES=4.7, FDR=0). RNA processing (NES=-6.5, FDR=0) and translation (NES=-5.8, FDR=0) pathways were depleted in BT245MR cells, and DNA repair pathways (NES=-5.8, FDR=0) were depleted in GBM1MR cells. The MAPK inhibitor trametinib demonstrated increased effectiveness in BT245MR and GBM1MR cell lines versus wild-type controls (BT245 IC50 158.7nM (wt) vs. 56.0 (MR), p&amp;lt;0.05; GBM1 IC50 150.7 (wt) vs. 53.4 (MR), p&amp;lt;0.05). BT245MR and GBM1MR cells reliably form PDX tumors after injection into mice. CONCLUSION: BT245MR and GBM1MR represent novel in vivo models of radiation-resistant pHGG, with gene expression alterations consistent with an irradiated phenotype. GSEA and in vitro dose-response data suggest MAPK inhibition may be effective in radiation-resistant pHGG. We are currently conducting in vivo experiments to validate increased trametinib sensitivity in these models.
IMMU-04. Transcriptional analysis reveals distinct microenvironmental subgroups across pediatric nervous system tumors
Authors: Arash Nabbi, Pengbo Beck, Alberto Delaidelli, Derek A Oldridge, Sumedha Sudhaman, Kelsey Zhu, S Y Cindy Yang, David T Mulder, Jeffrey P Bruce, Joseph N Paulson, Pichai Raman, Yuankun Zhu, Martin Silll, Sebastian Brabetz, Sander Lambo, Pascal D Johann, Adam C Resnick, Poul H Sorensen, David Malkin, Marcel Kool, David T W Jones, Stefan M Pfister, Natalie Jäger, Trevor J Pugh
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Recent clinical trials of immune checkpoint inhibitors indicated 5-11% response rate in pediatric patients depending on cancer type and expression of target proteins. Currently, a systematic analysis characterizing the immune microenvironment of childhood tumors is lacking. The main objective of this study is to uncover the features of immune microenvironment in pediatric nervous system tumors (pedNST). METHODS: We compiled transcriptomes of 925 tumors from three initiatives, Therapeutically Applicable Research To Generate Effective Treatments (TARGET, n = 149), International Cancer Genome Consortium (ICGC, n = 195) and Children Brain Tumor Tissue Network (CBTN, n = 581). We analyzed the performance of immune deconvolution tools and used publicly available datasets to define immune genesets. We conducted a consensus analysis to assign genes to cell-types and identify immunological groups. RESULTS: We found wide variability in immune infiltration across and within cancer types ranging from cold tumors such as medulloblastoma (2.7% infiltrate) to infiltrated entities such as neurofibroma (22.6%). Consensus clustering revealed four distinct immune clusters. The pediatric inflamed group (10%) included MYCN non-amplified neuroblastoma and ATRT. The myeloid-predominant group (30%) showed decreased infiltration of lymphoid cells but enrichment of myeloid cell genesets. The pediatric-cold group (42%) harbored no enrichment of immune genesets and included 72% of ependymomas and 65% of medulloblastomas. The immune excluded group (18%) showed depletion of immune cell-types and included sonic-hedgehog medulloblastoma. 71% of pedNST belonged to the lymphocyte depleted or immunologically quiet clusters, indicating the cold immune microenvironment in pedNST compared to adult cancers. CONCLUSION: We report characteristics of the immune microenvironment in pedNST. We found an overall cold microenvironment with low lymphocyte infiltration in this population compared to common adult cancers. We identified ~10% of tumors harboring a relatively inflamed microenvironment. Our data uncover characteristics of immune infiltration in pediatric tumors with potential implications to guide therapy.
Long-term survival projections of loncastuximab tesirine-treated patients in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Mehdi Hamadani, Christopher N. Graham, Laura Liao, Katherine H Zhang, Hannah Strat, David Ungar, Weiyun Z. Ai, Lei Chen, Carmelo Carlo-Stella
Journal: Journal of Clinical Oncology (2022)

e19551 Background: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA approved CD19-directed antibody-drug conjugate for R/R DLBCL. From the LOTIS-2 trial primary data cut (April 6, 2020), overall response rate was 48.3% and median overall survival (OS) was 9.9 months. The OS Kaplan-Meier (KM) plot displayed a survival plateau suggesting the presence of long-term survivors (LTS). Survival analyses were conducted on a more mature data cut (March 1, 2021; median follow-up = 1.7 years, follow-up completeness at median = 81%) to estimate the percentage of LTS and expected lifetime survival (mean OS) for lonca-treated patients. Methods: Consistent with studies of other R/R DLBCL treatments, identified through a literature review, parametric and mixture cure models were fit utilizing multiple distributions. Flexible cubic spline (hazard scale 1-3 knots) and non-mixture cure analyses were also conducted. Age- and gender-matched United States life table hazards were used in projections for LTS and to ensure modeled hazards were not less than the general population. Best-fit models were determined through fit statistics, KM and fitted curve overlays, and clinical plausibility. The best-fit model from each method was a candidate for overall best fit. A hybrid model following the best-fit parametric/spline model to a defined time point and switching to general population mortality was also constructed. Results: Mixture and non-mixture cure models fit best (individual best fits gamma and Weibull, respectively). Parametric and spline models (individual best fits log-normal and 2 knot models, respectively) did not fit the observed data well nor fit the clinical expectation of long-term survival. Due to better fit, spline models were used in the hybrid model. LTS from the mixture cure and non-mixture cure models were 24-26%. Mixture cure, non-mixture cure, and hybrid model with a 2-year switch point were consistent in survival predictions (6.11-6.23 years). In a sensitivity analysis with 3-year switch point in the hybrid model, the estimated survival was shorter due to the switch point being below the observed survival plateau. Table presents full survival results and fit statistics. Conclusions: The observed survival plateau suggests lonca-treated patients may include LTS. Mixture cure, non-mixture cure, and hybrid models fit the trial data well and align on survival projections (6.11-6.23 years). Additional follow-up may help refine the switch point of the hybrid model and confirm presence of LTS.[Table: see text]
Leucine-tRNA-synthetase-2-expressing B cells contribute to colorectal cancer immunoevasion
Authors: Zhiqiang Wang, Zhou Lu, Shengli Lin, Jie Xia, Ziwen Zhong, Zhangjuan Xie, Yun Xing, Jingbo Qie, Mengxia Jiao, Yifan Li, Haoyu Wen, Pengyuan Zhao, Dan Zhang, Pinghong Zhou, Jiawen Qian, Feifei Luo, Luman Wang, Hongxiu Yu, Jie Liu, Jie Gu, Ronghua Liu, Yiwei Chu
Journal: Immunity (2022)
Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence
Authors: Kristine Misund, Davine Hofste op Bruinink, Eivind Coward, Remco M. Hoogenboezem, Even Holth Rustad, Mathijs A. Sanders, Morten Rye, Anne-Marit Sponaas, Bronno van der Holt, Sonja Zweegman, Eivind Hovig, Leonardo A. Meza-Zepeda, Anders Sundan, Ola Myklebost, Pieter Sonneveld, Anders Waage
Journal: Leukemia (2022)

Abstract We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR &lt; 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.
Progress and perspective on hydrogen sulfide donors and their biomedical applications
Authors: Zi‐Long Song, Lanning Zhao, Tao Ma, Alsiddig Osama, Tong Shen, Yilin He, Jianguo Fang
Journal: Medicinal Research Reviews (2022)

Abstract Following the discovery of nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H 2 S) has been identified as the third gasotransmitter in humans. Increasing evidence have shown that H 2 S is of preventive or therapeutic effects on diverse pathological complications. As a consequence, it is of great significance to develop suitable approaches of H 2 S‐based therapeutics for biomedical applications. H 2 S‐releasing agents (H 2 S donors) play important roles in exploring and understanding the physiological functions of H 2 S. More importantly, accumulating studies have validated the theranostic potential of H 2 S donors in extensive repertoires of in vitro and in vivo disease models. Thus, it is imperative to summarize and update the literatures in this field. In this review, first, the background of H 2 S on its chemical and biological aspects is concisely introduced. Second, the studies regarding the H 2 S‐releasing compounds are categorized and described, and accordingly, their H 2 S‐donating mechanisms, biological applications, and therapeutic values are also comprehensively delineated and discussed. Necessary comparisons between related H 2 S donors are presented, and the drawbacks of many typical H 2 S donors are analyzed and revealed. Finally, several critical challenges encountered in the development of multifunctional H 2 S donors are discussed, and the direction of their future development as well as their biomedical applications is proposed. We expect that this review will reach extensive audiences across multiple disciplines and promote the innovation of H 2 S biomedicine.
Gastrointestinal adverse effects of combined checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Rahul Karna, Smit Deliwala, Balasubramanian Ramgopal, Palash Asawa, Rahul Mishra, Babu P. Mohan, Dheera Grover, Tanisha Kalra, Jaideep Bhalla, Ushasi Saraswati, Thejus Jayakrishnan, Dulabh K. Monga, Manish Dhawan
Journal: Journal of Clinical Oncology (2022)

e14591 Background: Combined immune checkpoint inhibitors (ICPI) have revolutionized treatment of solid tumors. Their use can lead to treatment-related adverse events (TRAEs) resulting in hospital admissions, treatment discontinuation and increased morbidity. We aim to evaluate gastrointestinal (GI) TRAEs of different combination ICPI. Methods: A comprehensive search of multiple databases from inception to October 2021 was performed. Phase 2 and 3 trials assessing safety and efficacy of combined ICPI in solid tumors were included. Trials reporting concurrent use of chemotherapy, immunosuppressants, targeted therapy, or sequential ICPI therapy were excluded. Primary outcome was pooled luminal, hepatic and pancreatic TRAEs. A meta-analysis of proportions was done for outcomes using a random-effects model. I 2 % was used to assess heterogeneity. Results: Out of 3696 citations screened, 53 trials reporting TRAEs in 6186 patients were included. Data from 41 study arms of 35 trials in nivolumab plus ipilimumab (N+I), 15 study arms of 15 trials in durvalumab plus tremelimumab (D+T), 4 study arms of 3 trials in pembrolizumab plus ipilimumab (P+I). The most common indications for combined ICPI were melanoma (26.4%) and lung cancer (24.5%). Pooled GI TRAE rates from the D+T, P+I and two different dosing combinations of N+I are shown in the table. Conclusions: Our study provides pooled data of TRAEs from different combination ICPI use in solid tumors and demonstrates high incidence of all grades and ≥ 3 GI TRAEs. Combined ICPI related TRAEs should be recognized early, as it may require treatment discontinuation. Further studies are required to assess overall impact of TRAEs on treatment course and outcomes.[Table: see text]
Outcomes of cisplatin dosing strategies in locally advanced non-nasopharyngeal head and neck squamous cell carcinoma treated with definitive concurrent chemoradiation in a safety-net hospital.
Authors: Jennifer Minkyoung Lee, Shuchismita Roy Satpathy, Farah Shah, Katie LaBarbera, Eutiquio Gutierrez
Journal: Journal of Clinical Oncology (2022)

e18064 Background: For patients with locally advanced non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) not amenable for resection, concurrent chemoradiation with cisplatin is the standard of care. Most popular dosing strategies for cisplatin include bolus dosing once every three weeks for a total of three cycles and once a week for seven cycles. Randomized studies comparing efficacy and tolerability of these dosing strategies have been conflicting. We examined how different dosing strategies affect outcomes in our institution, a safety-net hospital serving the medically underserved population in a large metropolitan area. Methods: We conducted a retrospective chart review of patients diagnosed with HNSCC from January 2015 to July 2021 in our institution. Patients with biopsy proven HNSCC with oral cavity, oropharyngeal, laryngeal, or hypopharyngeal primary tumor sites treated with definitive concurrent chemoradiation with cisplatin were included in the study. Those who received cisplatin bolus dosing were identified as Arm A and weekly dosing identified as Arm B. Primary outcome studied was 12-month event-free survival (EFS). We controlled for stage at diagnosis, age, p16 positivity, smoking status, treatment delay or premature discontinuation, and number of comorbidities. Secondary outcomes were rates of treatment delay or discontinuation, and median cisplatin dose received. To determine whether a preliminary association exists, a Pearson Chi-Square test for association of treatment type to 12-month EFS was utilized. To control for potential confounding variables the Mantel-Haenszel test was used on each confounder. Results: A total of 51 patients were included in the study, 36 (70.6%) with bolus and 15 (29.4%) with weekly cisplatin. After controlling for confounding variables listed above, there was no statistically significant association between Arm A or Arm B and 12-month EFS (p = 0.324). Delay or discontinuation rate for Arm A was 10 out of 36 patients (27.8%) and for Arm B was 5 out of 15 patients (33.3%). The difference in these rates were not statistically significant (p = 0.743). The median cisplatin dose received for Arm A was 300 mg/m2 and 280 mg/m2 for Arm B. Conclusions: In our institution, there was no difference in 12-month EFS or rates of treatment delay or discontinuation between patients who underwent definitive concurrent chemoradiation with bolus versus weekly cisplatin (p = 0.324). This has a significant impact on practical management of concurrent chemoradiation in our resource limited setting.
T-Cell Immunotherapy against Mutant KRAS for Pancreatic Cancer
Authors: Cornelis J.M. Melief
Journal: New England Journal of Medicine (2022)

Pancreatic ductal adenocarcinoma is the deadliest of all common cancers. The reasons for this are the advanced cancer stage by the time symptoms are noted and the occult presence of micrometastases in the liver and elsewhere at the time of initial surgical treatment. In addition, systemic therapy with chemotherapy rarely cures systemic disease, and immunotherapy with T-cell checkpoint inhibitors is notoriously ineffective. Therefore, the study reported by Leidner et al.1 in this issue of the Journal is remarkable because it shows deep and durable tumor shrinkage in a heavily pretreated patient who received an infusion of autologous T cells transduced . . .
An early warning system for emerging SARS-CoV-2 variants
Authors: Lorenzo Subissi, Anne von Gottberg, Lipi Thukral, Nathalie Worp, Bas B. Oude Munnink, Surabhi Rathore, Laith J. Abu-Raddad, Ximena Aguilera, Erik Alm, Brett N. Archer, Homa Attar Cohen, Amal Barakat, Wendy S. Barclay, Jinal N. Bhiman, Leon Caly, Meera Chand, Mark Chen, Ann Cullinane, Tulio de Oliveira, Christian Drosten, Julian Druce, Paul Effler, Ihab El Masry, Adama Faye, Simani Gaseitsiwe, Elodie Ghedin, Rebecca Grant, Bart L. Haagmans, Belinda L. Herring, Shilpa S. Iyer, Zyleen Kassamali, Manish Kakkar, Rebecca J. Kondor, Juliana A. Leite, Yee-Sin Leo, Gabriel M. Leung, Marco Marklewitz, Sikhulile Moyo, Jairo Mendez-Rico, Nada M. Melhem, Vincent Munster, Karen Nahapetyan, Djin-Ye Oh, Boris I. Pavlin, Thomas P. Peacock, Malik Peiris, Zhibin Peng, Leo L. M. Poon, Andrew Rambaut, Jilian Sacks, Yinzhong Shen, Marilda M. Siqueira, Sofonias K. Tessema, Erik M. Volz, Volker Thiel, Sylvie van der Werf, Sylvie Briand, Mark D. Perkins, Maria D. Van Kerkhove, Marion P. G. Koopmans, Anurag Agrawal
Journal: Nature Medicine (2022)
Packing a Punch against PD-L1
Authors: Claudia Capparelli, Andrew E. Aplin
Journal: Cancer Discovery (2022)

Antibodies targeting immune checkpoints have made major advances in cancer therapy, but their use can be limited by immune-related adverse effects. The introduction of small-molecule immune-checkpoint inhibitors represents an alternative to improve the current antibody-based immune therapies. See related article by Koblish et al., p. 1482 (3).